S-nitrosylation/activation of COX-2 mediates NMDA neurotoxicity

Proc Natl Acad Sci U S A. 2008 Jul 29;105(30):10537-40. doi: 10.1073/pnas.0804852105. Epub 2008 Jul 23.

Abstract

Glutamate/N-methyl-d-aspartate (NMDA) receptor-mediated neurotoxicity involves cyclooxygenase (COX)-2. We demonstrate that this neurotoxicity reflects activation of COX-2 by S-nitrosylation after selective binding of neuronal nitric oxide synthase (nNOS) to COX-2. nNOS, via its PDZ domain, binds COX-2 with the generated NO S-nitrosylating and activating the enzyme. Selective disruption of nNOS-COX-2 binding prevents NMDA neurotoxicity.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Biotin / chemistry
  • Brain / metabolism
  • Cell Death
  • Cerebellum / metabolism
  • Cyclooxygenase 2 / metabolism*
  • Enzyme Activation
  • Humans
  • Membrane Proteins / chemistry
  • Mice
  • N-Methylaspartate / toxicity*
  • Neurons / metabolism
  • Nitric Oxide Synthase Type II / metabolism
  • Protein Binding
  • Receptors, N-Methyl-D-Aspartate / chemistry*
  • Receptors, N-Methyl-D-Aspartate / metabolism

Substances

  • Membrane Proteins
  • Receptors, N-Methyl-D-Aspartate
  • N-Methylaspartate
  • Biotin
  • Nitric Oxide Synthase Type II
  • Cyclooxygenase 2